1. Field of the Invention
This invention pertains to a process for making alpha-anomer enriched 3,5-hydroxy protected-1-halo-2-deoxy-2,2-difluoro-D-ribofuranosyl derivatives.
2. State of the Art
Fluorine substitution has been investigated extensively in drug research and biochemistry as a means of enhancing the biological activity and increasing the chemical or metabolic stability of nucleosides. The replacement of a hydrogen by fluorine in a bioactive molecule is expected to cause minimal steric pertubations with respect to the molecule's mode of binding to receptors or enzymes and aid in overcoming the chemical and enzymatic instability problems of nucleosides. Nucleosides are typically synthesized by coupling a ribofuranosyl derivative with a purine or pyrimidine nucleobase. Synthetic reactions leading to many nucleosides involve stereochemical inversion of the ribofuranosyl configuration at the anomeric position. When applied to making alpha-anomer enriched starting material, this inversion provides increased amounts of biologically important beta-anomer nucleosides.
U.S. Pat. No. 4,526,988 describes a process for making 3,5-hydroxy protected-1-halo-2-deoxy-2,2-difluoro-D-ribofuranosyl derivatives by displacing the C1-acetate of 3,5-bis(t-butyldimethylsilyloxy) 2-deoxy-2,2-difluororibofuranose with a hydrogen halide such as hydrogen bromide or hydrogen chloride at -50.degree. C. to about 0.degree. C. The resulting compound is then coupled with a purine or pyrimidine base to form an anomeric mixture of nucleosides.
There continues to be a need for a stereoselective process for preparing alpha-anomer enriched 1-halo-2-deoxy-2,2-difluror-D-ribofuranosyl derivatives useful in stereoselective coupling reactions used to prepare anti-neoplastic and/or antiviral nucleoside agents.
Accordingly, one object of the present invention is to provide a stereoselective process for preparing alpha-anomer enriched 3,5-hydroxy protected-1-halo-2-deoxy-2,2-difluoro-D-ribofuranosyl derivatives.
Another object of the present invention is to provide a stereoselective process for preparing alpha-anomer enriched 3,5-hydroxy protected-1-halo-2-deoxy-2,2-difluoro-D-ribofuranosyl derivatives in high yields.